12-52519085-C-T

Variant names:

• chr12-52519085-C-T
• rs147498164
• NM_000424.4:c.631G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000424.4(KRT5):​c.631G>A​(p.Val211Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,208 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (35 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.375
• Publications: 2 publications found

Genes affected

KRT5 (HGNC:6442): (keratin 5) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT5 Gene-Disease associations (from GenCC):

• Dowling-Degos disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• epidermolysis bullosa simplex 1A, generalized severe

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• Dowling-Degos disease 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• epidermolysis bullosa simplex 1B, generalized intermediate

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 1C, localized

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 2B, generalized intermediate

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• epidermolysis bullosa simplex 2E, with migratory circinate erythema

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303401 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005289972).
• BP6: Variant 12-52519085-C-T is Benign according to our data. Variant chr12-52519085-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1610/152336) while in subpopulation AFR AF = 0.0371 (1541/41576). AF 95% confidence interval is 0.0355. There are 30 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	NM_000424.4	MANE Select	c.631G>A	p.Val211Met	missense	Exon 2 of 9	NP_000415.2	P13647

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	ENST00000252242.9	TSL:1 MANE Select	c.631G>A	p.Val211Met	missense	Exon 2 of 9	ENSP00000252242.4	P13647
	KRT5	ENST00000552629.5	TSL:1	n.729G>A		non_coding_transcript_exon	Exon 2 of 7
	KRT5	ENST00000551188.5	TSL:5	c.32G>A	p.Cys11Tyr	missense	Exon 1 of 6	ENSP00000449783.1	H0YIN9

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1606 AN: 152218 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00273 AC: 687 AN: 251476 AF XY: 0.00205

Gnomad AFR exome AF: 0.0394

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00101 AC: 1478 AN: 1461872 Hom.: 35 Cov.: 34 AF XY: 0.000825 AC XY: 600 AN XY: 727234

African (AFR) AF: 0.0388 AC: 1298 AN: 33480

American (AMR) AF: 0.00112 AC: 50 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112000

Other (OTH) AF: 0.00177 AC: 107 AN: 60392

GnomAD4 genome AF: 0.0106 AC: 1610 AN: 152336 Hom.: 30 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74482

African (AFR) AF: 0.0371 AC: 1541 AN: 41576

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00549 Hom.: 5

Bravo AF: 0.0122

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00352 AC: 428

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Epidermolysis bullosa simplex (1)
-	-	1	KRT5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.68
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.38
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.47
Sift	Benign	0.056	T
Sift4G	Benign	0.12	T
Polyphen		0.49	P
Vest4		0.25
MVP		0.79
MPC		0.43
ClinPred		0.028	T
GERP RS		1.4
PromoterAI		0.013	Neutral
Varity_R		0.083
gMVP		0.81
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147498164; hg19: chr12-52912869; COSMIC: COSV106087920; COSMIC: COSV106087920;